1. Field of the Invention
The present invention relates to a new chemical compound for effectively reducing or eliminating the release of acetylcholine (ACh) from the presynaptic nerve terminal of the cholinergic synapse.
Acetylcholine is a neurotransmitter substance, ubiquitous to the animal kingdom, which mediates transmission of electrical impulses from the presynaptic nerve terminal to the postsynaptic target cell whether it be nerve, muscle or organ cell. ACh mediates both inhibitory and excitatory responses depending upon the type of synapse. Synapses are functional junctions between a presynaptic nerve terminal and the postsynaptic membrane of the target cell. Anatomically these cholinergic junctions are comprised of a pre and postsynaptic membrane nexus where said membranes are separated by a microscopic gap or synaptic cleft.
Contained within the presynaptic terminal of the nerve are vesicles which contain ACh. When the presynaptic terminal is depolarized by electrical activity in the presynaptic nerve, such as in a typical monosynpatic excitatory cholinergic synapse, minute quantities of ACh are released from the vesicles to the synaptic cleft. The synaptic vesicles uptake ACh from the nerve cell cytoplasm by active transport across the vesicular membrane in order to replenish the ACh released during repetitive firing of the presynaptic nerve.
The ACh from the synaptic cleft binds to receptors on the postsynaptic membrane which results in an electrical or biochemical response of the target cell, and thus, an effective chemically mediated transmission of the presynaptic electrical impulse is completed to the postsynaptic cell.
The details of the function of acetylcholine and the microanatomy of the synapse has been widely studied. Consequently, many compounds exist for enhancing and inhibiting the effect of ACh by various mechanisms. These mechanisms include both the reduction and the elimination of release of ACh at the presynaptic terminal as well as inhibition of its receptor mediated effect at the postsynaptic membrane. Additionally, the effect of ACh can be enhanced by inhibiting the breakdown of ACh postsynaptically by acetylcholine esterase (AChEase). Those compounds that are effective in blocking acetylcholine esterase effectively block neuroconduction by preventing postsynaptic repolarization. Many common pesticides inhibit the postsynaptic metabolism of acetylcholine by AChEase.
Compounds that affect the action of ACh either presynaptically and postsynaptically also have clinical value as the cholinergic synapse is found in the central nervous system and at the neuromuscular junction of man. Such cholinergic synapses are also partially involved in neural control of the heart and other organs.
2. Prior Art
One such drug for blocking conduction at the neuromuscular junction in mammals is 2-(4-Phenylpiperidino)-cyclohexanol (AH 5183) which is a tertiary base having the following chemical structure: ##STR2## It is believed that AH 5183 inhibits the uptake of newly synthesized ACh into the synaptic vesicles thus producing failure of neurotransmission [see I. G. Marshall, Br. J. Pharmac., Vol. 38, pp. 503-516 (1970)]. While the AH 5183 provides an important research and clinical tool, it is desirable to produce a more effective compound for blocking presynaptic release of acetylcholine. Such a compound would be effective in lower concentrations from those effective for AH 5183.